Much of our daily behavior is controlled by stimuli (cues) associated with rewards that promote survival - for example, they attract us to sources of food and to potential mates. However, such cues can also promote maladaptive behavior. Food cues can instigate overeating, and cues associated with drug rewards motivate drug use and instigate relapse, thus contributing to addiction. Cues associated with rewards (conditional stimuli, CSs) powerfully motivate both normal and maladaptive behavior only if they are attributed with incentive motivational properties (incentive salience), and thus acquire the ability to act as incentive stimuli. In preliminary studies we made two novel observations: (1) the conditional stimulus properties of reward cues are not sufficient for them to also act as incentive stimuli, and (2) there is large variation in the propensity of individual rats to attribute incentie salience to food and drug cues, and thus to motivate behavior. These two observations lead to an innovative hypothesis, never explored, which is that individuals prone to attribute Incentive salience to drug cues will have particular difficulty resisting such cues, and thus be especially vulnerable to addiction. The purpose of this Program Project is to test this hypothesis, to study the operation of neurobiological systems that may underlie this variation, and to determine the relationship between this phenotype and other traits that may confer vulnerability to addiction. Thus, Project 1 primarily involves behavioral studies to determine if it is possible to predict, pror to any drug experience, which individuals are prone to attribute incentive salience to drug cues and whether these individuals are especially likely to develop addiction-like behavior. Project 2 focuses on whether this individual variation is related to variation in dopamine signaling in the nucleus accumbens, using fast scan cyclic voltammetry, and Project 3 uses electrophysiological recordings to determine whether this is further reflected in neural encoding in the main output of the accumbens, the basal forebrain/ventral pallidum. Finally, Project 4 links these subcortical systems with cortical, cognitive control systems and will explore cortical mechanisms that may account for cognitive vulnerabilities in individuals prone to attribute incentive salience to rewar cues. PUBLIC HEALTH RELEVANCE: Addiction is a major public health problem in the United States. The goal of this Project is to use a preclinical model to delineate the psychological and neurobiological basis of individual differences in vulnerability to develop addiction-like behavior as this will help identify risk factors that will aid in the development of targeting interventionsand treatments.